Targeting the BBB to treat CNS inflammation
靶向 BBB 治疗中枢神经系统炎症
基本信息
- 批准号:8826187
- 负责人:
- 金额:$ 28.31万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-09-25 至
- 项目状态:未结题
- 来源:
- 关键词:AddressAffectAnimal ModelAnimalsAutoimmune DiseasesAutopsyBiological MarkersBiological PreservationBiopsy SpecimenBloodBlood - brain barrier anatomyBlood VesselsBrainCNS autoimmunityCXCL11 geneCXCL12 geneCXCR4 ReceptorsCell PolarityCellsCellularityClinicalCuesDepositionDiffusionDiffusion Magnetic Resonance ImagingDiseaseDrug TargetingEdemaEncephalitisEndothelial CellsEndotheliumEnhancing LesionExhibitsExperimental Autoimmune EncephalomyelitisExperimental DesignsGadoliniumGeneticHumanImageImmuneIn SituIn VitroInfiltrationInflammationInflammatoryInvestigationLeadLesionLeukocyte TraffickingLeukocytesLifeLocationLymphocyteMagnetic Resonance ImagingMediatingModalityModelingMolecularMovementMultiple SclerosisMultiple Sclerosis LesionsMusMyelinNeuraxisOutcomePathogenesisPatientsPermeabilityProcessPublishingReceptor SignalingRelapseRoleSignal TransductionSiteSurfaceT-LymphocyteTestingTh1 CellsTissuesTranslationsTransport VesiclesVascular Permeabilitiesaxon injurybasecell motilitychemokinecytokinegadolinium oxidehuman tissueimaging modalityin vivointravital imagingintravital microscopymembrane polaritymigrationmonocyteneuroimagingneuroinflammationnovelreceptorresearch studyspectrographsphingosine 1-phosphatetraffickingtranscytosistwo-photon
项目摘要
Project 2 will determine how targeting molecules that regulate permeability and polarity at
central nervous system (CNS) endothelial barriers impacts neuroinflammation, as assessed via
novel neuroimaging modalities with murine models of multiple sclerosis (MS). We have shown
that endothelium in MS lesions exhibits altered polarity, displaying the abluminal chemokine
CXCL12 aberrantly along luminal surfaces. Abluminal CXCL12 normally serves to limit
leukocyte entry whereas luminal expression of CXCL12 is associated with increased activation
of its signaling receptor CXCR4 on infiltrating leukocytes. We showed that the scavenging
CXCL12 receptor, CXCR7 (also expressed by CNS endothelium), is a critical regulator of
leukocyte entry via internalization of CXCL12 from abluminal surfaces. In preliminary studies,
we have also found that sphingosine 1-phosphate (S1P) signaling via S1P2 disturbs abluminal
expression of CXCL12, which then disrupts immune privilege. Thus, mice with targeted deletion
of S1P2 or administered a specific antagonist, JTE-013, show reduced migration of leukocytes
into the CNS parenchyma during EAE. We hypothesize that alterations in membrane polarity of
CXCL12 at CNS endothelial barriers promote leukocyte capture and migration into the CNS,
contributing to the establishment of disease cycles in relapsing-remitting forms of CNS
autoimmunity. We have identified several molecules that regulate this process, leading to
reversal of apicobasal expression of the localizing cue, CXCL12. In this proposal, we will
examine the roles of CXCR7 and S1P2 in lymphocyte trafficking and inflammation in CNS
autoimmune disease using novel imaging modalities including two-photon intravital
microscopy and longitudinally using Diffusion Basis Spectrum Imaging (DBSI), which
distinguishes and quantitates cellularity and edema in live mice (see Project 1) and
examination of autopsied human MS patient and control CNS tissues.
We expect DBSI to be more sensitive than Gd enhancement to inflammation, including in the
setting of less profound blood-brain barrier alterations. To determine the relationships between
endothelial and immune cell (Th1 versus Th17) interactions and loss of BBB integrity, we will
directly compare results utilizing intravital imaging to DBSI and Gd enhancement in the same
animals. To address mechanisms by which endothelial cell polarity and localizing cues are
induced by interactions with inflammatory cells, we will utilize in vitro and in situ approaches with
human tissues. Thus, Aim 1 will determine whether CXCR7-mediated internalization of CXCL12
requires infiltration with Th1 versus Th17 cells during EAE. Aim 2 will determine whether S1P2-
mediated reversal of endothelial cell polarity leads to increased T cell capture and entry during
EAE, and Aim 3 will examine the relationship between CXCR7 and S1PR2 activation and T cell
migration at the BBB in MS. The experimental design of Project 2 will define how DBSI
determined cellularity and edema changes responding to various degrees of BBB abnormality
and cell infiltration in EAE mice.
项目2将确定如何靶向调节渗透率和极性的分子
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Robyn S Klein其他文献
West Nile virus: crossing the blood-brain barrier
西尼罗河病毒:穿越血脑屏障
- DOI:
10.1038/nm1204-1294 - 发表时间:
2004-12-01 - 期刊:
- 影响因子:50.000
- 作者:
Michael S Diamond;Robyn S Klein - 通讯作者:
Robyn S Klein
Infectious diseases research in 2024: insights into dementia
2024 年传染病研究:对痴呆症的见解
- DOI:
10.1016/s1474-4422(24)00497-6 - 发表时间:
2025-01-01 - 期刊:
- 影响因子:45.500
- 作者:
Robyn S Klein - 通讯作者:
Robyn S Klein
Robyn S Klein的其他文献
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{{ truncateString('Robyn S Klein', 18)}}的其他基金
2023 Neuroimmune Communication in Health and Disease Gordon Research Conference and Gordon Research Seminar
2023健康与疾病中的神经免疫通讯戈登研究会议暨戈登研究研讨会
- 批准号:
10609280 - 财政年份:2022
- 资助金额:
$ 28.31万 - 项目类别:
Research Program Award (R35 Clinical Trial Optional) - Dr. Robyn Klein NINDS
研究计划奖(R35 临床试验可选)- Robyn Klein NINDS 博士
- 批准号:
10397683 - 财政年份:2021
- 资助金额:
$ 28.31万 - 项目类别:
Research Program Award (R35 Clinical Trial Optional) - Dr. Robyn Klein NINDS
研究计划奖(R35 临床试验可选)- Robyn Klein NINDS 博士
- 批准号:
10239672 - 财政年份:2021
- 资助金额:
$ 28.31万 - 项目类别:
Astrocyte innate immune mechanisms of post-viral cognitive dysfunction
病毒后认知功能障碍的星形胶质细胞先天免疫机制
- 批准号:
10115451 - 财政年份:2020
- 资助金额:
$ 28.31万 - 项目类别:
Innate immune mechanisms of virologic control and recovery from flavivirus encephalitis
黄病毒脑炎病毒学控制和恢复的先天免疫机制
- 批准号:
10247164 - 财政年份:2020
- 资助金额:
$ 28.31万 - 项目类别:
Mechanisms of sex differences in blood-brain barrier biology
血脑屏障生物学中性别差异的机制
- 批准号:
9090530 - 财政年份:2016
- 资助金额:
$ 28.31万 - 项目类别:
Mechanisms of sex differences in blood-brain barrier biology
血脑屏障生物学中性别差异的机制
- 批准号:
9204440 - 财政年份:2016
- 资助金额:
$ 28.31万 - 项目类别:
Targeting the BBB to treat CNS inflammation
靶向 BBB 治疗中枢神经系统炎症
- 批准号:
9275040 - 财政年份:2008
- 资助金额:
$ 28.31万 - 项目类别:
Targeting the BBB to treat CNS inflammation
靶向 BBB 治疗中枢神经系统炎症
- 批准号:
8741885 - 财政年份:2008
- 资助金额:
$ 28.31万 - 项目类别:
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